Preparatory Problems 44th

a) In a 25 mL Erlenmeyer flask, dissolve 1.0 g of ferrous ammonium sulfate hexahydrate, (NH₄)₂Fe(SO₄)₂∙6H₂O, in 3 mL of H₂O to which has been added 3 drops of 6 M H₂SO₄.

2. While continuously swirling the flask, add 5.0 mL of 1 M oxalic acid (H₂C₂O₄), and carefully heat the mixture to boiling (it is important to continuously swirl the flask while heating). Remove the flask from the hot plate and let the solid settle to the bottom of the flask.

3. Separate the solid product from the liquid by decantation: Do not disturb the solid product on the bottom of the flask. (Transfer the liquid to an Erlenmeyer flask and label as Liquid Waste). To wash the solid product, add ~3 mL of hot water to the flask (heat water in the Erlenmeyer flask up to about 80 ^oC on a hot plate), swirl the mixture, allow the mixture to settle and pipette off the liquid layer without disturbing the solid product (transfer liquid to the Liquid Waste container). Repeat the washing step one more time.

1. 
   To the wet solid, add 2 mL of 2 M potassium oxalate (K₂C₂O₄).
   
2. 
   With the flask in a 40 ^oC water bath, carefully add 2 mL of 6% H₂O₂ (continuously swirl the flask).
   
3. 
   Transfer the flask to a hot plate, add 1.5 mL of 1 M oxalic acid (H₂C₂O₄), and bring the mixture to a boil. Let the mixture boil for 1 min.
   
4. 
   Remove the flask from the heat and cool to room temperature.
   
5. 
   Separate the solid from the liquid using gravity filtration (collect the filtrate in a clean, 50-mL Erlenmeyer flask).
   
6. 
   Cool the filtrate in an ice-water bath. To precipitate the product from the solution, add 8 mL of ethanol to the filtrate and swirl the flask.
   
7. 
   Collect the solid product by vacuum filtration.
   
8. 
   Air-dry the crystals (alternatively, dry the crystals between two sheets of filter paper).
   
9. 
   Transfer the dry crystals to a clean, dry pre-weighed vial. Determine the mass of crystalline iron(III) oxalate complex produced.
   

1. 
   Place ~0.02 M KMnO₄ solution into a 10 mL burette. Into a 125-mL Erlenmeyer flask, add about 0.020 g of precisely weighed sodium oxalate. To this Erlenmeyer flask, add 20 mL of water and 5 mL of 6 M sulfuric acid (H₂SO₄). Warm up the content of the flask in a hot water bath (maintained at ~80 °C).
   
2. 
   Titrate the sodium oxalate solution using the ~0.02 M KMnO₄ solution; stop the titration when addition of the last drop of KMnO₄ changes the color of the titrated solution to light-pink, and the color persists for ca. 1 minute. Record the volume of KMnO₄ used for this titration, and determine the molarity of KMnO₄ solution.
   

1. 
   Into a 125 mL Erlenmeyer flask, add ~0.020 g of the precisely weighed iron(III) oxalate product obtained in Part A. To this Erlenmeyer flask add 20 mL of water and 5 mL of 6 M sulfuric acid (H₂SO₄). Warm the content of the flask in a hot water bath (maintained at ~80 °C).
   
2. 
   Titrate the hot solution in the flask with potassium permanganate of known concentration until a slight pink color that persists for ~30 sec. (use the solution standardized in Part B, Step 1). Record the volume of permanganate used for titration.
   

1. 
   Write down the equation of the chemical reaction that occurs in Part A, Step 1. Explain the role of sulfuric acid in this preparative procedure.
   
2. 
   Calculate the percentage of oxalate in the iron(III) oxalate complex. Determine the composition of the synthesized iron(III) oxalate complex (select one of three possible structures provided in the Introduction).
   
3. 
   Calculate the yield of iron(III) oxalate complex you obtained in Part A.
   
4. 
   Write balanced equations of chemical reactions that were used in Part B, Step 2.
   

The compounds you are making are traditionally synthesized in solvents such as dichloromethane or toluene over the course of many hours, often while boiling the reaction solution the entire time. In contrast, you are performing these same reactions using a benign solvent with reaction times of less than 15 min at room temperature. Our solvent, ethyl lactate (EL), is derived from renewable resources and is biodegradable. These reactions have been optimized previously by adjusting the polarity of the EL with water to attain the best combination of product quality and reaction speed. A few drops of lactic acid (LA), an acid found naturally in dairy products and in fatigued muscles, is used as a catalyst in some of the reactions.

• 
  Ethyl lactate
  
• 
  Lactic acid
  
• 
  Sodium chloride
  
• 
  Substituted aniline (see below)
  
• 
  Substituted aldehyde (see below)
  
• 
  Ethanol
  
• 
  Sodium tetrahydridoborate
  
• 
  Methanol
  
• 
  Hydrochloric acid (6 M)
  
• 
  Dichloromethane
  
• 
  TLC solvent: 50:50 ethyl acetate/hexanes
  

• Graduated cylinders, 10 mL (2)

• Beral pipets (6)

• Beakers, 50 mL (2)

• Hot plate

• Spatulas

• Buchner filter funnel with filter flask and filter paper

• Small flasks for recrystallization (2)

• Melting point apparatus and capillaries

• Small vials with caps (2)

• Vials with caps (preferably without liner), 20 mL (2)

• UV lamps (optional)

• TLC spotters

• TLC plates (silica with fluorescent indicator A254)

• Chamber for TLC development

• Magnetic stirrer

• Ice water bath
Experimental Directions for Imine Preparation:

1. 
   The reactants. Select a pair of reactants.
   

ii. Draw the structure of each compound and of the imine expected from this pair of reactants.

2. 
   Begin chilling 50 mL of brine (saturated aqueous NaCl) and 50 mL of distilled water in an ice bath.
   
3. 
   Reaction solvent. Find the proper solvent ratio for your reaction in the table of reactants above. Solvent ratios are expressed as % ethyl (L)-lactate in distilled water. The total volume of the solvent is 5.0 mL unless otherwise specified. Measure the volumes of ethyl lactate and water in a graduated cylinder. If you need lactic acid (LA), add the indicated number of drops. Mix thoroughly.
   
4. 
   Prepare your reactants. Label two 50-mL beakers. Then, follow the set directions corresponding to the phases of your reactants. For the steps marked with an asterisk* check volumes in the table of reactants above.
   

Weigh the mass corresponding to 0.010 mol of the aniline directly into a labeled beaker; do the same for the aldehyde using a second labeled beaker.

*Add 2.0–2.5 mL of your solvent to both beakers. Be certain to leave about 0.5–1.0 mL solvent on reserve to use as a rinse.

Warm the beakers gently in the hood to dissolve both solids. This part should only take a few seconds. Mix thoroughly, and allow both solutions to cool to room temperature.

Weigh the mass corresponding to 0.010 mmol of the aniline in a labeled beaker; do the same for the aldehyde using a second labeled beaker.

*Add 3.5 mL of your solvent to the beaker containing the solid. Add 1.0 mL solvent to the beaker containing the liquid. Leave the remaining 0.5 mL solvent on reserve to use as a rinse. Mix thoroughly. Heat gently to dissolve the solid then allow the solution to cool to room temperature. Do not heat the liquid.

If two liquids:

Weigh the mass corresponding to 0.010 mol of the aniline directly into a labeled beaker; do the same for the aldehyde using a second labeled beaker.

Add 2.0–2.2 mL of your solvent to both beakers. Be certain to leave about 0.6–1.0 mL solvent on reserve to use as a rinse. Mix thoroughly. No heat is necessary.

5. Reaction. Do this next step as quickly as possible! Combine the solutions from two beakers and swirl a few times to mix. Some of the reactions are complete within seconds. Immediately use 0.5 mL solvent to rinse the beakers and add the rinse to the reaction beaker. Quickly, swirl the solution in the beaker a few times to make sure it is completely homogeneous. All of step 5 should be completed in less than 5 s. Record the “combine” time.

6. Observe. Let the reaction mixture sit undisturbed for up to 15 min. Watch carefully, and record all observations. Note the exact time you see first crystals, and label this time as “begin crystallization”.

Once crystal formation appears to be complete, note the time again and label it as “end crystallization”. Record the color of the solid at this point.

Let the reaction sit undisturbed another 5 min. Note whether or not there is a color change (some reactions may become a lighter color, and you should indicate this). Then, put the reaction beaker in an ice bath for 5 min. Note the times.

7. Wash: Add 10 mL of ice-cold brine to your solid. Use a clean spatula to transfer the solid gently in the brine until there are no solid chunks remaining. Some products are very compact, and you might need to scrape the surface of the solid gently to avoid chunks. You should end up with a suspension.

8. Vacuum filter this mixture.

9. Rinse and vacuum filter again: Rinse the beaker with 10 mL of ice-cold distilled water and then pour this liquid evenly over the crystals in your Buchner funnel. This step will ensure that the surface of the crystals is rinsed of any compounds adhering to the surface of the crystals. Scrape any residue with a spatula and transfer it to the crystals in the Buchner funnel. Reconnect the vacuum hose to draw the liquid through the filter. Discard the filtrate into the waste container.

10.Recrystallize. Dry your crystals as well as possible on the filter, then recrystallize your crude product from ethanol or methanol to obtain a pure sample.

11.Weight and Determine the Melting Point: Allow the recrystallized product to dry as well as possible on the Buchner funnel and then obtain the melting point. Weigh your dried product.

12.Fluorescence (optional): Many of the imines have a beautiful fluorescence. To observe this, follow the procedure below:

a) Transfer pea-sized portions of your crude product into two small vials (with caps). Label one vial as “W” and the other as “HCl”.

b) Add two drops of distilled water to the small vial labeled “W”. Add two drops 6 M HCl to the vial labeled “HCl”. Cap both vials tightly and allow the samples to sit undisturbed for at least 5 min. (The solids will not dissolve.) Note any color changes. Take the vials to a dark room. Turn your vials upside down and evaluate the fluorescence of both samples while the room is completely dark. The water-containing vial will serve as the control for the acid-containing vial. Record your observations.

Long wave UV: use the UV lamp set to 365 nm.

Short wave UV: use the UV lamp set to 254 nm. Do not look into the UV lamp when it is on-it can damage your eyes.

Warning: Do not look into the UV lamp when it is on-it can damage your eyes.
Experimental Directions—Imine Reduction:
The toxicities of the imines and amines are unknown. In addition to goggles and a lab coat wear gloves throughout the experiment.

1. 
   Yield and Stoichiometry: Based on the amount of imine to be used, calculate the theoretical yield of reduced product.
   
2. 
   Prepare at least six TLC spotters. Store the spotters in a clean, dry beaker until you are ready to use them.
   
3. 
   Prepare your imine TLC standard: Place about 0.05 g of your imine in a small vial. Dissolve in about 2 mL of dichloromethane. Cap tightly to keep the solvent from evaporating.
   
4. 
   Reduction and Workup:
   

b) Leave a small amount of imine in the original vial so that you can do color and melting point comparisons later.

c) Into a small vial weigh 0.2–0.3 g NaBH₄. Cap tightly.

d) Add 5 mL methanol to the 20 mL vial with your imine. Add a small magnetic stir bar to the vial, cap loosely and begin stirring. The sample will not dissolve but will form a suspension.

e) With a spatula, add about 1/5 of the NaBH₄ to the methanol suspension of the imine. Cap the vial LOOSELY. The reaction is exothermic; it is accompanied by evolution of hydrogen gas. Capping tightly could result in your vial exploding. Not capping at all can result in evaporation of methanol.

f) While waiting for the bubbling to end, perform TLC analysis of your imine standard. Spot a tiny amount at your start point, let the solvent evaporate, and then use the UV lamp at 254 nm to verify you have enough sample. Develop the plate in 50:50 ethyl acetate/hexanes. Afterward, visualize with the UV lamp. Calculate the R_f value.

g) After the bubbling subsides, add another 1/5 of the NaBH₄. Repeat this process until all of the NaBH₄ has been used. The whole process should take 10–15 minutes.

h) At some point during the addition steps, your imine will briefly dissolve and then a pale or white precipitate will immediately form. Record all of your observations.

i) Once the bubbling has completely stopped, do another TLC. This time, you will spot two lanes. One lane will contain a fresh aliquot of the imine standard used for the first TLC. The other lane will contain the product mixture, which you will prepare for TLC analysis as follows:

Use a Pasteur pipet to transfer 1–2 drops of the final suspension to a small vial. Dissolve this mixture in 1–2 mL of dichloromethane. Use this solution to spot the plate. Again, use the UV lamp to verify you have enough sample spotted. Develop and visualize the plate as before. Once you have finished the TLC analysis, draw sketches of both plates in your report. Staple the plates on top of the corresponding pages that you hand in at the end of lab.

j) Add 10 mL 5% sodium bicarbonate to your reaction mixture. Mix thoroughly and filter the resulting solid.

k) Once all solid has been transferred to the filter paper, rinse the solid with 10 mL of cold distilled water. Allow the sample to air dry. You might want to recrystallize the product from methanol.

5. Analysis of the Reduction Product:

a) Obtain the melting point. Some of the melting points may be rather high.

b) If possible, obtain ¹H and ¹³C NMR spectra.
Treatment of Data

a) Give the structures for the substituted aniline, the aldehyde, the imine, and the reduction product.

b) Report the melting points of the imine and the reduction product.

c) Optional: Report the ¹H NMR and ¹³C spectrum of the imine and the reduction product. Report your observations of the fluorescence on the imine.

• L-Ascorbic acid (abbreviated HAsc)

• Potassium hexacyanoferrate(III) (potassium ferricyanide), K₃[Fe(CN)₆]

• Aqueous hydrochloric acid solution, 0.120 mol·L^–1

• Deionized water

Compound	State	S-Phrase	R-Phrase
K3[Fe(CN)6]	Solid	50(B) 61	32, 52, 53
HCl(aq), 0.12 M	Solution in water	26 36 37 39 45	23 25 34 38

Apparatus and Glassware

• Analytical balance (± 0.0001 g)

• Volumetric flasks (2), 10 mL or 25 mL

• UV-visible spectrophotometer capable of measuring absorbance at 416 nm

• Spectrophotometric cuvette, 1 cm path length

• Plastic Beral pipettes, 1 mL (4), graduated in increments of 0.25 mL

1. Prepare stock solutions of ascorbic acid (~0.060 mol∙L^–1) and of potassium ferricyanide (~6.0  10^–3 mol∙L^–1) (10 or 25 mL each). The concentrations need not be exactly as stated, but you should record the exact concentrations of the stock solutions.

2. Using the Beral pipettes to dispense the solutions, mix 0.75 mL deionized H₂O, 1.50 mL aqueous HCl, and 0.50 mL of the ascorbic acid stock solution and place the solution in a cuvette. If you have a single-beam spectrophotometer, blank the spectrophotometer using this solution. If you have a double-beam spectrophotometer, make up a second identical solution and use this as the reference sample.

3. Initiate the reaction by adding 0.25 mL of the ferricyanide stock solution to the above mixture and mixing thoroughly. If your cuvette has a lid that seals tightly, you can mix the solution in the cuvette itself. If the cuvette does not have a tight-fitting lid (or has a volume less than 3 mL), you will need to mix the solution in a small vial, then transfer a portion of the mixed solution into the cuvette. As quickly as possible, replace the cuvette in the spectrophotometer and begin measuring the absorbance at 416 nm as a function of time.

4. Record absorption at 416 nm, A₄₁₆, as a function of time over the course of 10 minutes. In the early part of the reaction (when the absorbance is changing rapidly), you should record the absorbance frequently (every 10 seconds or so), but as the reaction slows, you can make less frequent readings if you wish (every 30 seconds or so).

5. Repeat steps 2–4 as needed to explore the effect on the rate of varying the ascorbic acid concentration in the range [HAsc] = 0.005–0.015 mol∙L^–1 and of the acidity in the range [H⁺] = 0.01–0.10 mol∙L^–1. If the reaction is slower than the initial experiment, you may need to extend the monitoring period to 15 or 20 minutes in order to allow the reaction to go nearly to completion (the absorbance, A₄₁₆, should fall below 0.02).

a) Give a balanced chemical equation for the oxidation of ascorbic acid by hexacyanoferrate(III) ion. Include a structural formula for the oxidation product of ascorbic acid.

b) Determine the reaction order in Fe(CN)₆^3–, and justify your determination.

c) Determine the reaction order in HAsc, and justify your determination.

d) Ascorbic acid readily ionizes to form the ascorbate anion, Asc^–, with a pK_a = 4.10 (K_a = 7.9·10^–5). Indicate which proton in ascorbic acid is readily ionized and explain why it is so acidic.

e) The dependence of the reaction rate on [H⁺] is somewhat complex (it does not exhibit a simple, integer order). A plausible explanation for this is that both ascorbic acid (HAsc) and ascorbate anion (Asc^–) can be oxidized by hexacyanoferrate(III) ion, but that they have different reactivities. Use this model to analyze your data quantitatively to determine the relative reactivity of ascorbate anion and ascorbic acid toward Fe(CN)₆^3–.

In this experiment, you will explore the Mannich reaction between 2,2-dimethyl-1,3-diaminopropane with excess 2,4-di-tert-butylphenol and formaldehyde. Because the starting amine has two primary amino groups, one could envision many different possible Mannich products that could be formed in this reaction. In fact, one product is formed selectively and can be isolated in moderate yield. You will be asked to suggest a structural formula of this product based on its ¹H NMR spectra provided below.

• 2,2-Dimethyl-1,3-diaminopropane, NH₂CH₂C(CH₃)₂CH₂NH₂

• 2,4-di-tert-butylphenol, C₆H₃(C[CH₃]₃)₂OH

• Aqueous formaldehyde, 37% (w/v)

• Ethanol

• Methanol

• Hexane/ethyl acetate mixture for TLC (3:1 v/v)

Compound	State	S-Phrase	R-Phrase
2,2-Dimethyl-1,3-diaminopropane	Liquid	26 36/37/39 45	10 22 24 35
2,4-di-tert-butylphenol	Solid	22 36	22 36 37 38
Formaldehyde(aq)	37 % solution in water	1/2 26 36/37/39 45 51	23/24/25 34 40 43
C2H5OH	Liquid	7 16 24 25 36 37 39 45	11 20 21 22 36 37 38 40
CH3OH	Liquid	1/2 7 16 36/37 45	11, 23/24/25 39/23/24/25
Hexanes	Liquid	53 45	45 22
Ethyl acetate	Liquid	16 26 33	11 36 66 67